8Evidence of inaction hard to ferret out extent and timingTimeMissing values imputed with LOCF. 9Rarely apparent in survival curves 10Time to event 11What I am not going to talk about

MCAR, MAR, not MAR

Ignorable/non-ignorable

The effect of missing data on inference

In sample surveys

In experiments

In randomized clinical trials

Detailed methods of dealing with missing data

12What I will discuss

Once over lightly of the methods at hand

Why others dont care about missing values

Why our protocols encourage missing data

What we can do to prevent missing data

Even though prevention is boring

13Underlying principle

Our method of imputation shouldnt give us better results than what we would have seen from the complete cases

14The cards in our deck binary outcomes

Just ignore the missing observations

Impute missing on basis of

Proportion in own group

Best case all pbo fail all rx succeed

Worst case all pbo success all rx fail

Proportion in placebo group (not unreasonable guess)

Proportion in opposite group (reasonable worst case)

Multiple imputation

15Problems with the binary cards

Too many degrees of freedom

Some methods overstate effect

Some methods understate effect

Some methods are unreasonably pessimistic

16Loss of 3 lines of vision

Two groups treated and control

120 eyes per group (one per person)

40 in placebo 20 in treated

Look at relative risk (

Missing equal in both groups

17Loss of 3 lines of vision impute own groupImputation leads to increased sample size hence false precision. 18Binary example loss of 3 lines of vision1.130.31100 of missing behave the same way not reasonable. 19Binary example loss of 3 lines of vision0.6Not unreasonable to assume that untreated act like placebo. Best reasonable case 20Binary example loss of 3 lines of vision0.67Opposite arm is worst reasonable case. 21What do binary cards do for us

Participation in this study is entirely voluntary. Your treatment and your doctors attitude toward you will not be affected should you decide not to participate in this study

You will be asked to return for follow-up visits and to provide follow-up information.

If you agree to participate, you may withdraw from the study at any time without affecting any benefits to which you would otherwise be entitled.

34Permissive protocols encourage missing data

Drop-outs will not be replaced

Suggests that it would be ok to replace them

Suggests that analysis will ignore them

Expect 10 drop out, therefore increase sample size by 10

The primary analysis will use the intent-to-treat pop

The ITT pop is defined as all those randomized who

The ITT pop is defined as the evaluable group

35Language about withdrawal an outcome trial

The reason that a subject discontinues from the study will be recorded in the Case Report Form.

A discontinuation occurs when an enrolled subject ceases participation in the study, regardless of the circumstances, prior to completion of the protocol.

The final evaluation required by the protocol will be performed at the time of study discontinuation.

36Outcome continuous measure at week 48

Subjects must be withdrawn from the study (i.e., from any further study medication or study procedure) for the following reasons

At their own or their legally authorized representatives request

If, in the investigators opinion, continuation in the study would be detrimental to the subject's well-being

Occurrence of an intolerable treatment-emergent adverse event as determined by the investigator and/or the subject

Failure of the subject to return to the study site for scheduled visits

Persistent noncompliance

Pregnancy

37Prevention of missing values

Education

What is the effect of various analytic methods

Why is missing important

Revise informed consent forms

Make protocols less permissive

38Education of investigators

Important to explain to investigators

need for follow-up

consequences to the study of failure to follow-up

39Improved informed consent document

Participation in this study is entirely voluntary. Your treatment and your doctors attitude toward you will not be affected should you decided not to participate in this study

If you agree to participate, you may withdraw from the study at any time without affecting any benefits to which you would otherwise be entitled.

You will be asked to return for follow-up visits and to provide follow-up information even if you are not taking study medication.

40Protocols

Be vigilant about permissive language

Distinguish between

Stopping meds

Stopping active visits

Withdrawing consent to be followed passively

Explain to investigators the importance of follow-up

(even for those who stop study medication)

41Typical language about withdrawal in protocols

The reason that a subject discontinues from the study medication will be recorded in the Case Report Form.

A discontinuation from the study occurs when an enrolled subject ceases participation a participant in the study dies, is permanently lost to follow-up, or withdraws consent, regardless of the circumstances, prior to completion of the protocol.

An final evaluation required by the protocol will be performed at the time of study discontinuation of study medication.

42But, if there are missing data

Choose analytic methods that

Dont add false precision

Are reasonably conservative

Are interpretable

Recognize that need for big increase in sample size

Phil Lavoris rule 1 missing observation needs three additional

So, if you expect 10 missing, inflate sample size by 1/3

43Conclusion homework assignment

Look at all your protocols

Look at all your model informed consent forms

Prevent permissive language in the future

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